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Clinical Trial
. 2020 May 11;13(1):47.
doi: 10.1186/s13045-020-00886-2.

Reactive cutaneous capillary endothelial proliferation in advanced hepatocellular carcinoma patients treated with camrelizumab: data derived from a multicenter phase 2 trial

Feng Wang  1   2 , Shukui Qin  3 , Xinchen Sun  4 , Zhenggang Ren  5 , Zhiqiang Meng  6 , Zhendong Chen  7 , Xiaoli Chai  8 , Jianping Xiong  9 , Yuxian Bai  10 , Lin Yang  11 , Hong Zhu  12 , Weijia Fang  13 , Xiaoyan Lin  14 , Xiaoming Chen  15 , Enxiao Li  16 , Linna Wang  17 , Ping Yan  17 , Jianjun Zou  17
Affiliations
Clinical Trial

Reactive cutaneous capillary endothelial proliferation in advanced hepatocellular carcinoma patients treated with camrelizumab: data derived from a multicenter phase 2 trial

Feng Wang et al. J Hematol Oncol. .

Abstract

Background: Association of immune-related adverse events with tumor response has been reported. Reactive cutaneous capillary endothelial proliferation (RCCEP) is the most common adverse event related to camrelizumab, an immune checkpoint inhibitor, but lack of comprehensive analyses. In this study, we conducted comprehensive analyses on RCCEP in advanced hepatocellular carcinoma (HCC) patients treated with camrelizumab monotherapy.

Methods: Data were derived from a Chinese nationwide, multicenter phase 2 trial of camrelizumab in pre-treated advanced HCC. The occurrence, clinicopathological characteristics, and prognostic value of RCCEP were analyzed.

Results: With a median follow-up of 12.5 months, 145 of the 217 camrelizumab-treated patients (66.8%) experienced RCCEP (all grade 1 or 2). RCCEP occurred on the skin surface, mainly on the skin surface of head, face, and trunk. RCCEP could be divided into 5 types including "red-nevus-like," "pearl-like," "mulberry-like," "patch-like," and "tumor-like," according to the morphological features. RCCEP biopsy and pathology showed capillary endothelial hyperplasia and capillary hyperplasia in dermis. Significant association between RCCEP occurrence with higher objective response rate was observed (19.3% vs. 5.6%; one-sided p = 0.0044). Compared with those without RCCEP, patients with RCCEP had prolonged progression-free survival (median PFS; 3.2 months vs. 1.9 months; one-sided p < 0.0001) and overall survival (median OS; 17.0 months vs. 5.8 months; one-sided p < 0.0001). In multivariable analyses, the development of RCCEP was significantly associated with prolonged PFS and OS after adjusting for baseline covariates. In addition, the landmark analyses of PFS and OS were consistent with the unadjusted analysis.

Conclusions: RCCEP occurred on the skin surface and was an immune response of skin capillary endothelial cells. RCCEP occurrence positively associated with outcomes of camrelizumab in advanced HCC.

Keywords: Anti–PD-1 antibody; Camrelizumab; Hepatocellular carcinoma; Immune-related adverse events; Reactive cutaneous capillary endothelial proliferation.

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Conflict of interest statement

Linna Wang, Ping Yan, and Jianjun Zou are employees of Jiangsu Hengrui Medicine Co., Ltd. Other co-authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Morphological classification of reactive cutaneous capillary endothelial proliferation
Fig. 2
Fig. 2
Pathological characteristics of RCCEP. a “red-nevus-like” RCCEP pathological tissue. b “pearl-like” or “tumor-like” RCCEP pathological tissue. Tissues were analyzed using hematoxylin and eosin (H&E) staining (× 400). RCCEP, reactive cutaneous capillary endothelial proliferation
Fig. 3
Fig. 3
“Pearl-like” RCCEP skin nodule histopathology and molecular marker detection. a Immunohistochemistry. b Immunofluorescence co-staining (red, VEGF-A; green, CD163; and blue, DAPI. Arrow: M2 macrophages expressing VEGF-A). RCCEP, reactive cutaneous capillary endothelial proliferation
Fig. 4
Fig. 4
Comparisons in survival between patients with and without RCCEP. a Kaplan-Meier curve of PFS. b Kaplan-Meier curve of OS. All 217 patients treated with camrelizumab were included in the analysis. RCCEP, reactive cutaneous capillary endothelial proliferation; PFS, progression-free survival; OS, overall survival
Fig. 5
Fig. 5
Landmark analysis of survival between patients with and without RCCEP. a Landmark survival analysis curve with 1.5 months as the cutoff time point. One hundred and ninety-five patients with PFS ≥ 1.5 months were included in the analysis. The RCCEP group consisted of patients with RCCEP within 1.5 months and the group without RCCEP consisted of patients without RCCEP within 1.5 months. b Landmark survival analysis curve with 3.0 months as the cutoff time point. One hundred and ninety patients with OS ≥ 3.0 months were included in the analysis. The RCCEP group consisted of patients with RCCEP within 3.0 months, and the group without RCCEP consisted of patients without RCCEP within 3.0 months. c Landmark survival analysis curve with 5.0 months as the cutoff time point. One hundred and sixty-nine patients with OS ≥ 5.0 months were included in the analysis. The RCCEP group consisted of patients with RCCEP within 5.0 months, and the group without RCCEP consisted of patients without RCCEP within 5.0 months. RCCEP, reactive cutaneous capillary endothelial proliferation; PFS, progression-free survival; OS, overall survival
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